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New method for synthesizing dasatinib

A technology of dasatinib and a new method, which is applied in the field of synthesizing dasatinib, can solve the problems of high production cost, harsh reaction conditions, and unfriendly environment, and achieve the effects of low production cost, mild reaction conditions, and environmental friendliness

Inactive Publication Date: 2011-04-13
SHANGHAI SYNCORES TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This method mainly has the following disadvantages: a, the route is long, and the economy is not good; b, the raw materials used are very industrialized raw materials
[0017]WO2007019210A1: This route can be produced industrially. The first disadvantage is that the yield of the first step reaction is low and the price of furochloric acid is high; To intermediate 21, solvents such as toluene and methanol are used in a large amount, and it is difficult to recycle, which is not friendly to the environment
[0027] (4) Preparation of compound 7 by hydrolysis and deprotection requires trifluoroacetic acid and trifluoromethanesulfonic acid, which are expensive
[0028] As can be seen from the above, this method has harsh reaction conditions, high risk of operation, high production cost, and is not suitable for large-scale industrial production

Method used

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  • New method for synthesizing dasatinib
  • New method for synthesizing dasatinib
  • New method for synthesizing dasatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Preparation of N-(2-chloro-6-methylphenyl)-2-[[6-chloro-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (Compound 7)

[0063] 13.2 g of compound 2-(6-chloro-2-methylpyrimidinyl-4-amino)thiazole-5-carboxylic acid and 100 ml of thionyl chloride were stirred and mixed at room temperature, 2 ml of DMF was added, and then heated under reflux for 4 hours Complete the reaction. Concentrate under reduced pressure to dryness, add 50ml of dichloromethane, add 6.9g of 2-chloro-6-methylaniline dropwise after cooling to 0°C, stir for 5 minutes after the addition, and then add dropwise 15ml of triethylamine. After dripping, the temperature was naturally raised to room temperature and stirred overnight, and a large amount of solid was precipitated. The mixture was concentrated to dryness, 1N sodium hydroxide was added and stirred for 15 minutes, filtered, the filter cake was washed twice with 100 ml of water and washed with 100 ml of methanol to obtain 12.5 g of light yellow solid ...

Embodiment 2

[0065] Preparation of N-(2-chloro-6-methylphenyl)-2-[[6-chloro-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (Compound 7)

[0066] 13.2 g of compound 2-(6-chloro-2-methylpyrimidinyl-4-amino)thiazole-5-carboxylic acid and 150 ml of toluene were stirred and mixed at room temperature, 20 ml of thionyl chloride were added, and then 1.0 ml of DMF , The temperature was raised to 80°C and reacted overnight. Concentrate under reduced pressure to dryness, then add 150 ml of toluene, and then remove toluene under reduced pressure to obtain a solid. Add 50ml of dichloromethane, after cooling to 0°C, add dropwise 6.9g of 2-chloro-6-methylaniline, stir for 15 minutes after the addition, and then add dropwise 15ml of triethylamine. Warm to room temperature and stir overnight. The mixture is concentrated to dryness under reduced pressure, then 1N sodium hydroxide is added and stirred for 15 minutes, filtered, and the filter cake is washed twice with 100 ml of water and washed with 100 m...

Embodiment 3

[0068] Preparation of N-(2-chloro-6-methylphenyl)-2-[[6-chloro-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (Compound 7)

[0069] 13.2 g of compound 2-(6-chloro-2-methylpyrimidinyl-4-amino)thiazole-5-carboxylic acid and 130 ml of dichloromethane were stirred and mixed at room temperature, 0.5 ml of DMF was added, and then cooled to 0°C. 28.0 ml of a dichloromethane solution of 2mol / L oxalyl chloride was added dropwise, after the addition, the temperature was raised to room temperature, and the reaction was continued to be stirred for 2.5 hours to complete the reaction. The reaction mixture was concentrated to dryness as much as possible, and then 150 ml of toluene was added, and concentrated under reduced pressure to obtain a solid. Add 50ml of dichloromethane, stir and mix. After cooling to 0°C, add 6.9g of 2-chloro-6-methylaniline dropwise, stir for 15 minutes after the addition, and then dropwise add 15ml of triethylamine. After dripping, warm to room temperature and ...

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Abstract

The invention discloses a new method for synthesizing dasatinib. The method comprises the following steps: a compound 38 and a compound 8 are subjected to amidation reaction to obtain a compound 7; and the compound 7 reacts with a compound 10 under alkaline condition to obtain dasatinib I. The method provided by the invention has the following advantages: the method is mild in reaction conditions, simple to operate, convenient for purification, low in production cost, environmental-friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a new method for synthesizing dasatinib. Background technique [0002] Dasatinib, the chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]- 2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide, its structural formula is as follows: [0003] [0004] Dasatinib is a polytyrosine kinase inhibitor, which is the first oral chemotherapy drug capable of inhibiting multiple configurations of tyrosine protein kinase Abl. At nanomolar concentrations, the drug inhibits multiple kinases of the BCR-ABL kinase family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-B. By inhibiting the above-mentioned kinases, dasatinib can inhibit the proliferation of leukemia cells in the bone marrow of CML and Ph+ ALL, but normal red blood cells, white blood cells and platelets can still continue to proliferate. [0005] The synthetic route of existing dasatinib (I) mainly contains...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
Inventor 李小鹏
Owner SHANGHAI SYNCORES TECH INC
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